Preparation and characterization of new C2- and C 1-symmetric nitrogen, oxygen, phosphorous, and sulfur derivatives and analogs of TADDOL. part III

Article abstract of DOI:10.1002/hlca.201200148

A brief overview is presented of the field of organocatalysis using chiral H-bond donors, chiral Bronsted acids, and chiral counter-anions (Fig. 1). The role of TADDOLs (=α,α,α′,α′-tetraaryl- 1,3-dioxolane-4,5-dimethanols) as H-bond donors and the importance of an intramolecular H-bond for acidity enhancement are discussed. Crystal structures of TADDOLs and of their N-, S-, and P-analogs (Figs. 2 and 3) point the way to proposals of mechanistic models for the action of TADDOLs as organocatalysts (Scheme 1). Simple experimental two-step procedures for the preparation of the hitherto strongest known TADDOL-derived acids, the bicyclic phosphoric acids (2 in Scheme 2) and of a phosphoric-trifluorosulfonic imide (9 in Scheme 4), are disclosed. The mechanism of sulfinamide formation in reactions of TADDAMIN with trifluoro-sulfonylating reagents is discussed (Scheme 3). pK_a Measurements of TADDOLs and analogs in DMSO (reported in the literature; Fig. 5) and in MeO(CH₂)₂OH/H₂O (described herein; Fig. 6) provide information about further possible applications of this type of compounds as strong chiral Bronsted acids in organocatalysis. Copyright

Full text of DOI:10.1002/hlca.201200148

Helvetica Chimica Acta – Vol. 95 (2012)
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Preparation and Characterization of New C2- and C1-Symmetric Nitrogen,
Oxygen, Phosphorous, and Sulfur Derivatives and Analogs of TADDOL
Part III
Some New Chiral Brønsted Acids for Organocatalysis and pKa Values in
MeOꢀ(CH2)2ꢀOH/H2O – A Survey
by Dieter Seebach*, Albert K. Beck, Hans-Ulrich Bichsel1), Arkadius Pichota2), Christof Sparr3),
Ralf Wꢀnsch3), and W. Bernd Schweizer
Laboratorium fꢀr Organische Chemie, Departement fꢀr Chemie und Angewandte Biowissenschaften,
ETH-Zꢀrich, Hçnggerberg HCI, Wolfgang-Pauli-Strasse 10, CH-8093 Zꢀrich
(phone: þ 41-44-632-2990; fax: þ 41-44-632-1144; e-mail: seebach@org.chem.ethz.ch)
A brief overview is presented of the field of organocatalysis using chiral H-bond donors, chiral
Brønsted acids, and chiral counter-anions (Fig. 1). The role of TADDOLs (¼a,a,a’,a’-tetraaryl-1,3-
dioxolane-4,5-dimethanols) as H-bond donors and the importance of an intramolecular H-bond for
acidity enhancement are discussed. Crystal structures of TADDOLs and of their N-, S-, and P-analogs
(Figs. 2 and 3) point the way to proposals of mechanistic models for the action of TADDOLs as
organocatalysts (Scheme 1). Simple experimental two-step procedures for the preparation of the hitherto
strongest known TADDOL-derived acids, the bicyclic phosphoric acids (2 in Scheme 2) and of a
phosphoric-trifluorosulfonic imide (9 in Scheme 4), are disclosed. The mechanism of sulfinamide
formation in reactions of TADDAMIN with trifluoro-sulfonylating reagents is discussed (Scheme 3). pKa
Measurements of TADDOLs and analogs in DMSO (reported in the literature; Fig. 5) and in
MeO(CH2)2OH/H2O (described herein; Fig. 6) provide information about further possible applications
of this type of compounds as strong chiral Brønsted acids in organocatalysis.
1. Introduction. – Asymmetric Counterion Catalysis. As part of the ongoing ꢁgold
rushꢂ [1] for applications of organocatalytic reactions, there is great interest in chiral
Brønsted acids. The borderlines between H-bond donors (sometimes called ꢁneutralꢂ
Brønsted acids), weakly acidic, ꢁstrongerꢂ, and ꢁhighly acidicꢂ Brønsted acids (Fig. 1,a)
are difficult to define, especially when we remember that there are no solvent-
separated ion pairs in an organic medium (cf. toluene), where the ions will be in
contact, for instance, by forming H-bonds with each other (Fig. 1,b). This was
masterfully demonstrated by an NMR investigation of the system (PhO)2PO2H/N-
phenylimines of PhCHO and acetophenone [2]. Apart from these delicate mechanistic
details, the exciting fact for the synthetic organic chemist is that many typical Lewis or
Brønsted acid-catalyzed textbook reactions can be carried out with chiral Brønsted
acids to become enantioselective. Formally, intermediate achiral cations with enantio-
1
)
)
)
Part of the Diplomarbeit (master thesis) of H.-U. B. (1997/1998), ETH Zꢀrich.
Part of the Ph.D. Thesis of A. P., ETH Dissertation No. 14015 (2000).
Postdoctoral Fellows 2011/2012 (C. S.) and 1996/1997 (R. W.), ETH Zꢀrich.
2
3
ꢃ 2012 Verlag Helvetica Chimica Acta AG, Zꢀrich

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Fig. 1. a) Selection of chiral H-bonding and Brønsted acidic compounds, and b) interactions with an
imine/iminium derivative
topic faces4) react with nucleophiles preferentially from one of the enantiotopic faces,
because the chiral counterion is blocking the other one, to put it in simple terms. In the
complex with the chiral counter-anion (or H-bond donor), the enantiotopic faces of the
electrophile become diastereotopic. This has been realized in recent years for a large
variety of systems, some of which are indicated in Fig. 2,a. So far, the focus has been on
iminium (including acyliminium and protonated nitrone) [4] and enoyl-iminium [5]
systems (including protonated pyridines [6] and quinolines [7]), conjugated and non-
conjugated carbonyl derivatives [8], and conjugatively stabilized carbocations [9]5).
4
)
Some use the term ꢁprochiralꢂ reactants. It is, however, inappropriate to call whole molecules
prochiral; see textbooks of stereochemistry (e.g., [3]).
It is impossible to do justice to all the contributors to this field in this Introduction. The ꢁmajor
playersꢂ in the area of chiral-counter-anion catalysis are (in alphabetical order): T. Akiyama, J. C.
Antilla, J. N. Johnston, B. List, M. Rueping, M. Terada, and H. Yamamoto. For a review article
entitled ꢁModulating the Acidity: Highly Acidic Brønsted Acids in Asymmetric Catalysisꢂ, see [9c].
5
)

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Fig. 2. Achiral cations with enantiotopic trigonal centers formally involved in chiral counter-anion
catalysis (a), in the ultimate challenge (b), and counter-cation-induced enantioselective phase-transfer
catalysis (c)
The ultimate challenge will be the enantioselective acid-catalyzed hydration of a simple
olefinic C¼C bond (Fig. 2,b). In this context, phase-transfer catalysis (PTC) [10] with
chiral counter-cations [11], a kind of umpolung of the above process, must be
mentioned (see the example in Fig. 2,c [12]).
2. Enantioselective H-Bonding Catalysis with TADDOLs. – The now classical type
of enantioselective H-bonding donor catalysis with chiral urea, and especially thiourea
derivatives was introduced by Jacobsen and has enjoyed numerous applications,
especially since the review article appeared in 2006 [13]. As in the counter-ion catalysis
[2], the mechanistic details may be more complicated than suggested by the simple
picture presented in Fig. 1,a [14]. Besides the ureas, small synthetic peptides have also
been successfully applied as H-bond-donor organocatalysts [15].
As indicated in Fig. 3,b and c, the TADDOLs (¼a,a,a’,a’-tetraaryl-1,3-dioxolane-
4,5-dimethanols) are more acidic (better H-bond donors) than simple benzhydrylic
alcohols due to an intramolecular H-bond (cf. the benzoic acid derivatives in Fig. 3,a).
Intramolecular H-bonds in the crystal structures of TADDOLs, and their derivatives

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Fig. 3. Increased acidity by H-bonding (a – c) and intramolecular H-bonding as found in X-ray crystal
structures of TADDOL derivatives and analogs (d). For the structures, see [16a,b] and references cited
therein. Interestingly, there is no H-bond between the OH and the ester group of the mono-
trifluoroacetate ester 1 of TADDOL (e); this carbonyl O-atom is a poor H-bond acceptor, and/or the
nine-membered H-bonded ring is unfavorable.
and analogs are collected in Fig. 3,d. An exception is the mono-trifluoroacetate 1 in
Fig. 3,e. TADDOLs are known to be able to form H-bond donorꢀacceptor complexes
with essentially every type of small molecules containing an amino, imino, aziridino,
oxaziridino N-atom, or a hydroxy, epoxy, ether, acetal, carbonyl, nitroso, or sulfoxide

Helvetica Chimica Acta – Vol. 95 (2012)
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Fig. 4. Hostꢀguest crystal structures of three TADDOLs (H-bond donors) with a ketone [17], a 1,2-
pyrazoline [18], and anisaldehyde [19] as H-bond acceptors with the corresponding CCDC (Cambridge
Crystallographic Data Centre) codes
O-atom, both in the solid (crystalline) state6) and in solution: when TADDOLs are
crystallized in the presence of racemic mixtures of H-bond acceptors, one enantiomer
can become a host in the lattice of the TADDOL crystal; for three examples, see Fig. 4.
There is a large number of crystal structures of this type, mainly determined by F.
Todaꢂs group6) (a search in the Cambridge Crystallographic Data Base as of February
2012 retrieved 142 examples). The ꢁclathrationꢂ of single enantiomers in TADDOL
crystals has been used for resolutions6), for dynamic resolutions (ꢁderacemizationsꢂ)
[21], and for performing enantioselective photoreactions within cystals. The H-bond
donorꢀacceptor couples are also present in solution, as evident from the fact that
TADDOLs can be used as NMR shift reagents for determining enantiomer ratios
[22]7).
In 2002, Rawal and co-workers described the first application of TADDOL (with
Arl ¼ naphthalen-1-yl) as an enantioselective H-bonding catalyst [19][23] for activa-
tion of aldehyde groups. Some representative examples are collected in Scheme 18).
6
)
For selected examples of guestꢀhost X-ray crystal structures of TADDOLs, see Scheme 6 in [20].
See also review articles by the Toda group cited in [16a] as ref. 26. Even CCl4 has been found to
form a clathrate with TADDOL; see reference 4 in [16b].
See also Scheme 5 in [20].
For quantum-mechanical investigations [25] of this type of catalysis, see especially Section 4.2.1 in
the Chem. Rev. article [25c].
7
8
)
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The observed addition from the Si-face9) of the aldehyde groups is compatible with the
crystal structure of the TADDOL (Arl ¼ naphthalen-2-yl)/anisaldehyde complex [19],
shown in Fig. 4,c) and with computational results8), according to which the OH ··· O¼C
H-bond is located next to a quasi-equatorial naphthalen-1-yl group in such a way that
the enantiotopic Re-face is sterically shielded from nucleophilic attack. It looks as if this
is a case, in which we have a chance to predict the stereochemical outcome of
enantioselective reactions by determining the crystal structures of the clathrates
formed by the organocatalyst and the electrophilic reactant, the H-bond acceptor.
3. TADDOL-Derived Brønsted Acids. – To the best of our knowledge, only one
type of strong Brønsted acids has been prepared from TADDOLs and used as
catalysts10): Akiyama et al. converted a series of seven TADDOLs to cyclic phosphoric
acid diesters (Scheme 2) and showed that a Mannich-type reaction was catalyzed by
these acids with enantioselectivities of up to 96 :4, if the imine substrate was derived
from an aromatic aldehyde and 2-amino-5-methylphenol [28]11). The TADDOP-acids
2 used as catalysts for this transformation were prepared by reaction of TADDOL with
PCl3, hydrolysis, and oxidation with I2. Voituiez and Charette have prepared another
series of TADDOP-acids [29] by a more elaborate sequence of steps. We describe
herein a two-step preparation of the parent acid 2a by chlorophosphorylation of
TADDOL (see previous paper [16b] in this series) and hydrolysis (Scheme 2).
It would be desirable to have additional H-bond donors and Brønsted acids of the
TADDOL skeleton, with acidities in between the parent TADDOL A (R1 ¼ R2 ¼ Me,
R3 ¼ Ph) and the phosphoric acids 2, or even more acidic derivatives12) than 2. There
are two ways of increasing the TADDOL acidity, as indicated in formula A: stronger
electronegative aryl (cf. C6F5) or non-aromatic groups (cf. CF3) could be introduced, as
shown by Berkessel and co-workers [33] (vide infra), or, heteroatoms XH with more
acidic H-atoms (cf. SH, NHCOR, NHSO2R) could be introduced by replacement of the
TADDOL OH groups. Replacement reactions of this type have been described by us
(see the first two parts of this series of publications [16a,b] and earlier papers cited
therein). In X-ray crystal structures, which are alluded to in Fig. 3,d, higher acidities of
sulfanyl and triflamido (¼trifluoromethanesulfonamido) groups are indicated by the
intramolecular H-bonding patterns detected in the solid state. In the late 1990s1–3), we
had prepared these more acidic derivatives not because we were ahead of our time,
foreseeing ꢁasymmetrical catalysis by chiral H-bond donorsꢂ [13] or ꢁasymmetric
counter-anion-directed catalysisꢂ (ACDC [5a – d]), but because we wanted to be able to
protonate less basic ꢁcarbanionoidꢂ species than lithium enolates, after we had found
9
)
For the Re/Si-nomenclature for describing stereochemical courses of reactions, see [3a][3b][3c][3d]
and [26].
10
)
We are also aware of only one case, in which TADDOL was used in enantioselective PTC: an
alanine imino-ester enolate of the type shown in Fig. 2,c (generated with NaOH or NaH in toluene
in the presence of TADDOL), was alkylated enantioselectively [27].
Formaldehyde-derived TADDOLs (such as the catalyst precursor in Scheme 2 with R1 ¼ R2 ¼ H)
were first prepared to lend higher acid stability to the system and to allow for better recovery –
under acidic conditions – of the TADDOL after catalytic usage [31].
An attempt to prepare a bis[sulfonic acid] from the dithiol analog of TADDOL was unsuccessful
[32].
11
12
)
)

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Scheme 2. An Enantioselective Brønsted Acid-Catalyzed Mannich Reaction, Producing a Special Type of
b-Amino Acid Derivatives [28], with a TADDOP-Acid Catalyst; Preparation [16b][28][29] of
TADDOP-Acids and a Crystal Structure of 2a (not showing H2O and THF molecules in the unit cell)
[29]. For a comparison with a Lewis acid-catalyzed variant of this Michael addition, see [30]. The acids
described in [29] were prepared to be used as precursors of enantioselective SimmonꢀSmith-like
cyclopropanating reagents.
out that stoichiomeric amounts of the parent TADDOL protonate the achiral Li-
14
enolate of b-methyl-a-tetralone with an enantioselectivity of 98 :2 [34]13
) )
15). The
progress made in the field of enantioselective protonations between 1995 and 2009 is
demonstrated by a comparison of two review articles on this subject [40][41].
Before turning to the acidities of the TADDOL-derived stronger acids, we should
like to present some interesting observations made when trying to prepare the
13
)
)
For an enantioselective enolate protonation (er 90:10), mediated by catalytic amounts of
TADDOLs and analogs, see [35].
For an industrial application of enantioselective enol/ketone tautomerization, see [36]. As far as we
know, the first catalytic enantioselective protonation of an enol intermediate was described by
Pracejus in 1960 (addition of MeOH to a ketene R1R2C¼C¼O with catalytic amounts of a chiral
amine [37]; see also a dendritic effect of this reaction [38]).
14
15
)
For the enantioselective protonation of a silyl enol ether by phenol in the presence of a typical
strong chiral Brønsted acid, (R*O)2P(S)NHTf (5 mol-%), see [39]; cf. also [7].

Helvetica Chimica Acta – Vol. 95 (2012)
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bis[triflamide] of TADDAMIN 3 (Scheme 3). When treated with excess trifluorome-
thanesulfonic anhydride (Tf2O)/Et3N, the diamine 3 gave the mono-triflamide 4 in
good yields, no bis[triflamide] was formed16). After reaction with excess TfCl/Hꢀnig
base (EtNiPr2; DIPEA), neither the mono- nor the bis[triflamide] was found. Rather,
complex mixtures of the products 5 – 7, plus unidentified compounds, were detected in
the crude product mixtures. With DBU (¼1,8-diazabicyclo[5.4.0]undec-7-ene) instead
of DIPEA as base, the major product was the sulfinamide 6 (see Table 2 in the Exper.
Part). The surprising formation of sulfinamides 6 and 7, the structures of which were
established by single-crystal X-ray analyses, can be rationalized by a mechnism
analogous to that proposed by Netscher and Bohrer for the formation of triflinates
(¼trifluoromethanesulfinates) from reactions of alcohols or phenols with Tf2O/Et3N
[42]; see Reaction a in Scheme 3: a mixed anhydride of sulfonic and sulfinic acid is
formed, which acts as a sulfinylating agent. As far as we can see, the formaldehyde
aminal group in 7 may arise from an impurity or from the solvent CH2Cl2. We carefully
checked the purity of the TfCl for Me-containing impurities, in vain; a methylamino
derivative, such as iPr2NMe, could be the source of the CH2 group in 7, as indicated in
Reaction b of Scheme 3, but we have no evidence for such an impurity in the Hꢀnig base
(DIPEA) used. A reaction with CH2Cl2 is not expected to occur under our reaction
conditions (2 – 4 equiv. of TfCl, ꢀ 408 to room temperature)17). Similarly surprising to
us was the formation of the bicyclic sulfuric diamide (¼sulfamide) 5, formally a
substitution of F3Cꢀ, under the reaction conditions (for details, see Table 2 in the Exper.
Part)18).
As Brønsted acids, which are expected [7][8a][39] to be more acidic than the
TADDOP-acids 2 (Schemes 2 and 4), we have also tried to prepare imides (cf. 9b) from
the TADDOP-acid chlorides 8. These acid chlorides turned out to be surprisingly inert
to nucleophilic replacement of chloride: i) they readily survived chromatography on
silica gel; ii) hydrolysis of the acid chloride 8b to the acid 2a (THF/H2O 1:1) required
heating at reflux for 24 h; iii) conversion of 8b to the amide 10 (THF/aq. NH4OH 1:1)
takes 60 h at room temparature; iv) the Cl/NHSO2CF3 substitution with acid chloride
8a (104 mg/TfNH2 (60 mg)/iPr2EtN (155 mg)/CDCl3 (0.3 ml)) was carried out by
16
)
Treatment of the mono-triflamide 4 with trifluoromethanesulfonating reagents also failed to
produce the bis[triflamide].
17
18
)
)
It is well-known that amines may react, even vigorously, with chlorinated solvents, see, e.g., [43].
Radical reactions, photochemical processes, and Ru-catalyzed transformations can lead to loss of
.
CF3 groups from triflic acid derivatives [44].

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Scheme 3. Results of the Reactions of TADDAMIN 3 with Tf2O and TfCl/Et3N or Hꢀnig Base. The
structures of the sulfinamides 6 and 7 are established by X-ray analysis. In the unit cell of the structure of
7, there is a molecule of Et2O (not shown here). Possible mechanisms for the formation of electrophilic
sulfinylating and (diisopropylamino)methylating reagents are shown in a and b, respectively (see also
accompanying text).

Helvetica Chimica Acta – Vol. 95 (2012)
1313
heating at 558 for 14 h, to give the ammonium salt 9a (for a crystal structure, see
Scheme 4)19). The sluggishness of the TADDOP-acid chlorides 8 in nucleophilic
substitution reactions may be discussed simply by considering, in a naive, ꢁfirst-orderꢂ
analysis, a trigonal bipyramidal intermediate 11, with the nucleophilically introduced
substituent Nu and the Cl-atom in apical positions, with an OꢀPꢀO bond angle20
)
widened from 1108 to ca. 1208, and with 1,5-repulsion (Newman strain [3e]) between
both, the Cl and the Nu group, and the neighboring quasi-axial Ph groups (see bottom
of Scheme 4). If the pentacoordinate intermediate 11 were really a high-energy species
in the rate-determining step, it would be responsible for the poor reactivity of the acid
chlorides 821). The ammonium salt 9a, obtained in two steps from the corresponding
TADDOL, can be purified by flash chromatography. In the unit cell of the crystal of
this imide, there is also a molecule of toluene (not shown in Scheme 4); the Hꢀnig base
ammonium ion is somewhat disordered, and the R3NꢀHþ H-atom forms a H-bond with
the P(O) O-atom (not with the N-atom or one of the SO2 O-atoms)22) of the counter-
anion. Samples containing the acid 9b were obtained by preparative TLC; the acid
should also be formed by treatment with ion-exchange material.
4. pKa Determinations in 2-Methoxyethanol/H2O 4 :1 and Comparison with Values
in Other Solvents. – The information on acidities of organic and inorganic compounds
is of central, paramount importance in chemistry (more than 200 years ago, G. de
´
Morveau stated ꢁTenir la definition des acides, cꢁest tenir la clef de la chimieꢂ [45]). Due
to poor solubility of most organic compounds in H2O, their acidities are determined in
non-aqueous media. Since the stability of the involved ions depends strongly on their
solvation and on the dielectric constant (DK) of the solvent, pKa values can only be
compared when determined in the same solvent (see the representative list of values
(relevant for the following discussion) in Table 1). For a given compound, the pKa value
in DMSO (DK 47) is always higher than that in H2O (DK 78), and the difference can
be as large as 15 and as small as 3 units23). Berkessel, OꢁDonoghue and co-workers have
recently published a thorough investigation of the acidities (in DMSO/2% H2O) of
acids of importance for organocatalysis [33], including the fluoro-activated derivatives
of TADDOL and analogs shown in Fig. 5.
19
)
Attempted triflation (Tf2O, TfCl) of the phosphoric acid amide 10, with two Me groups on the
dioxolane ring (a ketal of acetone), led to mixtures of products lacking the geminal Me groups
(NMR analysis). This is why we turned to the dioxolane derived from tartaric acid and
formaldehyde, in which this heterocyclic ring is much more stable towards aggressive electrophiles
(cf. [28]), Scheme 2, Footnote 11, and discussion of the lability of the TADDOL skeleton in Sect. 4
of [16b]).
20
21
)
)
For the crystal structure of 8b, see compound 23 in Fig. 2 of [16b].
For a case in which the TADDOL skeleton has a ligand-accelerating effect, see the ca. 1000-fold
activity of (iPrO)2Ti-TADDOLate as compared to (iPrO)4Ti in Lewis acid catalysis; for a discussion
of this effect, see Chapt. 10 in [20] and references cited therein.
22
23
)
)
Thus, in the crystal structure, the P(O) O-atom is the site of highest H-bond acceptor activity (and
anionic charge density?) of the phosphoryl-trifluorosulfonyl imide. If this would be the preferred
type of interaction also in solution of such imide anions, their achiral partners would be held close to
the chirality-inducing centers or axes (cf. Fig. 1).
For a useful compilation of the pKa values in H2O and DMSO with references, see [53].

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 4. Preparation, in Two Steps, of the TADDOP-Acid Derivatives 2a and 8 – 10 from TADDOLs,
Crystal Structures of 9a and 10, and a Pentacoordinate Intermediate, 11, in Phosphorylations of
Nucleophiles by an Acid Chloride, 8. The two different conformations in the unit cell of amide 10 are
shown.

Helvetica Chimica Acta – Vol. 95 (2012)
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Table 1. The pKa Values of Compounds with Functional Groups Occurring in the TADDOL Derivatives
and Analogs Shown in Figs. 5 and 6. The pKa values in DMSO (the Bordwell scale) are taken from [46],
the pKa values in H2O are taken from Marchꢂs textbook [47], and from monographs on amides [48], on
sulfonic acid derivatives [49], and on fluoro-compounds [50]. The values for protonated imines
R2C¼NHRþ and for the phosphoric acid diester (PhO)2P(O)OH are taken from [51] and [52],
respectively.
2 O
pKaH
2O
pKaH
Acid
pKDa MSO
Acid
pKDa MSO
AlkylꢀOH
ArylꢀOH
15 – 17
8 – 11
6 – 8
7 – 8
15.5
12.8
9.3
MeCONHPh
CF3CONHPh
PhCONH2
21.5
17.2
23.4
26.9
17.5
AlkylꢀSH
R2C¼NHRþ (R ¼ H, Alkyl)
MeOH
CF3CH2OH
(CF3)2CHOH
PhOH
H2NꢀCOꢀNH2
29.0
23.5
18.2
18.0
10.3
30.6
12.3
23.5
25.5
18.5
17.2
MeSO2NH2
10.8
11.8
9.0
10.0
11.4
8.4
6.3
7.6
4.5
1.9
MeSO2NHMe
MeSO2NHPh
PhSO2NH2
PhSO2NHMe
PhSO2NHPh
CF3SO2NH2
CF3SO2NHMe
CF3SO2NHPh
(PhO)2P(O)OH
10.0
6.5
16.2
9.7
PhSH
PhNH2
MeꢀCO2H
HꢀCONH2
MeꢀCONH2
MeꢀCSNH2
CF3ꢀCONH2
4.7
15.1
In the 1960s, Simon [54] developed an acidity scale in the solvent mixture 2-
methoxyethanol (ꢁMethylcellosolveꢂ, MCS)/H2O 4 :1 (DK 32). The values are
*
determined by titration with Et4NOH; the upper limit is pKMCS ca. 11, and the lower
*
limit is pKMCS ca. 3. The values obtained for H2O-soluble compounds are between 1 and
2.5 pKa units higher than those measured in pure H2O24). The pKMCS values for some of
*
the TADDOL-derived acids are collected in Fig. 6; for comparison, we have also
determined the values for BINOL and two bis[triflamides]25). As might have been
*
expected, the TADDOP-acid 2a is the most acidic compound of the series (the pKMCS
5.5 corresponds to a pKaH O between 3.0 and 4.5; cf. AcOH), closely followed by the
2
*
triflamido-thiol (5.7) and the triflamido-alcohol (5.9). We tried to determine the pKMCS
value for the imide 9b by titration of its ammonium salt 9b with HCl; there was no
*
inversion of the titration curve, which could mean that the pKMCS is outside of the lower
limit of ca. 3. The sulfanyl alcohol and the trifluoroacetamido thiol have remarkably
*
low pKMCS values of 8.9 and 7.4 (in the range of thiophenols), respectively.
Comparisons of the triflamide with its methylsulfanyl ether (5.7 vs. 9.7), and of the
sulfanyl alcohol with the sulfanyl ethers (8.9 vs. > 11) demonstrate the strong influence
of intramolecular H-bonding on the acidities of TADDOL derivatives (cf. Fig. 3), an
effect which is not detected for BINOL, and which is due to the unique conformational
lock caused by the two geminal diaryl moieties of the TADDOL scaffold, pushing the
24
*
)
)
For extensive tables with more than 1000 pKMCS values, see [55].
25
The acidimetric titrations were carried out by the Analytical Service Division of the Laboratorium
fꢀr Organische Chemie, ETH Zꢀrich.

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Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 5. Acidities of a TADDOL (Arl ¼ C6F5) and analogs, and of the BINOL phosphoric acid derivative
in DMSO/2% H2O [33]. Interestingly, the pKa value of the TADDOL is essentially the same as that of
decafluorobenzhydrol, and the crystal structure of this TADDOL shows that the exocyclic CꢀC bond has
the less frequently observed OꢀCꢀCꢀO gauche conformation with the OH groups over the dioxolane
ring, i.e., no intramolecular H-bond between the two HO groups, and thus no H-bond-induced increase
of acidity [33] (see the discussions in Sect. 1, and in [16a] (Sect. 3) and [16b] (Sect. 5). In the CF3 analog,
we see the familiar seven-membered-ring H-bond in the crystal [33]; note that this compound is by
12.5 pKDa MSO units more acidic than (CF3)2CHOH (HFIP, cf. Table 1).
OH-groups into close proximity. If we were to make an estimate for the pKaH O of the
2
parent TADDOL (Arl ¼ Ph), we would place it close to 13.
5. Conclusions. – The results presented here show that introduction of various
functional groups on the TADDOL backbone can provide Brønsted acids with a variety
of acidities between pKMCS 5.5 and 10.8 (corresponding to pKaH O 3.0 – 4.5 and 8.3 – 9.8).
2
*
Application of the principle of modulating the acidity of compounds of this type by
manipulations of the two heteroatomic substituents could provide further strong
Brønsted acids for applications in enantioselective counter-cation organocatalysis.
When considering that we can use TADDAMINs B (pKa > 30) for generating chiral
Li-amides for deprotonations (lithiations) [56], the statement may be justified that we
can cover the entire acid/base range from pKa > 30 all the way down to pKa 3 by placing
suitable functional groups (NH, SH, NHSO2CF3, P(O)(OH) C, D, E) on the scaffold,
which is common to all TADDOLs and their analogs26).
We gratefully acknowledge the contributions of the co-workers of the services of the Laboratorium
fꢀr Organische Chemie: Prof. Dr. B. Jaun, B. Brandenberg, and P. Zumbrunnen (NMR), Dr. W. Amrein,
26
)
No configuration is indicated in the formulae B – E because both enantiomers are equally readily
accessible from (R,R)- or (S,S)-tartaric acid.

Helvetica Chimica Acta – Vol. 95 (2012)
1317
*
Fig. 6. The pKMCS values of Brønsted acids derived from TADDOL. For comparison, the values of
BINOL and of two bis[trifluoro-sulfonamides] are also shown. For details of the pKa titration in
ethyleneglycol monomethyl ether/H2O 4 :1, see the accompanying text and [54][55]. The preparation of
the compounds shown here is described in the Exper. Parts of the present paper, and of Parts I and II of
this series of publications [16a,b].
H. U. Hediger, R. Hꢂfliger, and O. Greter (MS), and M. Schneider and D. Manser (acidimetric titrations,
elementary analyses, molecular weights). We also acknowledge the generous financial support by ETH
Zꢀrich and Novartis AG, Basel.
Experimental Part
1. General. Abbreviations: DBU, 1,8-Diazabicyclo[5.4.0]undec-7-ene; FC, flash chromatography;
h.v., high vacuum, 0.01 – 0.1 Torr; Tf2O, trifluoromethanesulfonic anhydride; TfCl, trifluoromethane-
sulfonyl chloride; THF was freshly distilled over K before use. Et3N was distilled over CaH2. CH2Cl2 was
used in puriss. quality. Solvents for workup and chromatography: pentane and hexane were distilled over
P4O10 or Sikkon (anh. CaSO4; Fluka), AcOEt over Sikkon, Et2O over KOH/FeSO4, and CH2Cl2 over
P4O10. PCl3 was distilled before use. All other reagents were used as received from Fluka or Aldrich. All
indicated reaction temp. were monitored with an internal thermometer (Ebro-TTX-690 digital

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Helvetica Chimica Acta – Vol. 95 (2012)
thermometer). TLC: Macherey-Nagel Alugram SIL G/UV254 or Merck 60 F254 silica gel plates; detection
by UV light (l 254 nm) or I2 , or by dipping in/spraying with phosphomolybdic acid soln.
(phosphomolybdic acid (25 g), Ce(SO4)2 · 4 H2O (10 g), H2SO4 (60 ml), H2O (940 ml)), followed by
heating. FC: Fluka silica gel 60 (0.040 – 0.063 mm), at ca. 0.3 bar. M.p.: Bꢀchi-510 apparatus;
uncorrected. Optical rotations: Perkin-Elmer 241 polarimeter (10-cm, 1 ml cell), at r.t. IR Spectra:
Perkin-Elmer-1620-FT-IR spectrometer, in cmꢀ1. NMR Spectra: Bruker AMX-500 (1H: 500 and 13C:
125 MHz), AMX-400 (1H: 400 and 13C: 100 MHz), Varian Gemini-300 (1H: 300, 13C: 75, and 19F:
282 MHz), Mercury-300 (1H: 300, 13C: 75, and 19F: 282 MHz) or Gemini-200 (1H: 200 and 13C: 50 MHz);
chemical shifts (d) in ppm downfield from TMS (d 0.0) as internal standard; J values in Hz. MS: VG
Tribrid (EI; 70 eV), VG ZAB-2 SEQ (FAB; 3-nitrobenzyl alcohol matrix), IonSpec Ultima (FT-ICR-
MALDI; 4.7 T; 2,5-dihydroxybenzoic acid matrix), Bruker REFLEX (TOF-MALDI; N2 Laser), or
Finnigan MAT TSQ 7000 (ESI) spectrometer; in m/z (% of basic peak). HR-MS: IonSpec Ultima (FT-
ICR-MALDI; 4.7 T; 2,5-dihydroxybenzoic acid matrix). Elemental analyses were performed by the
Microanalytical Laboratory of the Laboratorium fꢀr Organische Chemie, ETH Zꢀrich.
2. Preparation of the Compounds 1 and 4 – 7. {(4R,5R)-5-[(Hydroxy)(diphenyl)methyl]-2,2-
dimethyl-1,3-dioxolan-4-yl}(diphenyl)methyl 2,2,2-Trifluoroacetate (1). To a soln. of the parent TAD-
DOL A (R1 ¼ R2 ¼ Me, R3 ¼ Ph; 1.50 g, 3.21 mmol) in THF (15 ml) was added BuLi (4.70 ml, 7.07 mmol;
1.5m soln. in hexane) at ꢀ 758. The mixture was allowed to warm to r.t. (ca. 2 h), whereupon a colorless
precipitate was formed. After cooling to ꢀ 308, (CF3CO)2O (1.34 ml, 2.02 g) was added dropwise over
10 min. The mixture was allowed to warm to r.t., and stirred for further 2 h. The yellow soln. was washed
with sat. aq. NaHCO3 soln. (20 ml) and sat. aq. NaCl soln. (20 ml), and the aq. phase was extracted with
Et2O (2 ꢁ 30 ml). The combined org. phases were dried (Na2SO4), and the solvent was removed under
reduced pressure. The crude product was recrystallized (acetone, ꢀ 208) to afford 1 (1.16 g). After
partially removing the solvent from the mother liquor, further 1 (0.42 g) was obtained. Total yield: 1.58 g
(87%). Colorless crystals. M.p. > 1028 (dec.). [a]rD:t: ¼ ꢀ146.6 (c ¼ 1.04, CHCl3). IR (CHCl3): 3597w,
3063w, 3008w, 2936w, 1788s, 1710w, 1496m, 1448m, 1382w, 1371m, 1169s, 1148s, 1083m, 1050m, 1032w,
1
884m, 636w. H-NMR (200 MHz, CDCl3): 0.78 (s, Me); 0.86 (s, Me); 2.42 (br. s, OH); 5.08 (d, J ¼ 7.3,
CH); 5.69 (d, J ¼ 7.3, CH); 7.29 – 7.59 (m, 20 arom. H); 9.85 (br. s, NH). 13C-NMR (50 MHz, CDCl3):
27.10, 27.36, 76.56, 79.00, 80.56, 89.63, 111.15, 127.12, 127.18, 127.50, 127.95, 128.17, 128.55, 129.60, 129.79,
139.53, 141.79, 142.13, 147.69. Anal. calc. for C33H29F3O5 (562.59): C 70.45, H 5.20; found: C 70.32, H 5.49.
N-[{(4S,5S)-5-[(Amino)(diphenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}(diphenyl)methyl]-1,1,1-
trifluoromethanesulfonamide (4). A soln. of 3 (2.32 g, 5.0 mmol) in CH2Cl2 (450 ml) at ꢀ 708 was added
dropwise over 25 min to a soln. of Tf2O (2.0 ml, 12.0 mmol) in CH2Cl2 (30 ml). Then, a soln. of Et3N
(1.75 ml, 12.66 mmol) in CH2Cl2 (120 ml) was added during 3.5 h. After warming slowly to r.t. and stirring
overnight, the mixture was washed with H2O (2 ꢁ 50 ml) and sat. aq. NaCl soln. (2 ꢁ 50 ml), and dried
(MgSO4). The solvent was removed under reduced pressure, and the residue was purified by FC (SiO2
(100 g); pentane/Et2O 2 :1 ! Et2O) to yield 4 (2.50 g, 84%). Recrystallization from iPrOH/H2O afforded
4 (1.60 g, 54%). Colorless solid. M.p. 235 – 2378. Rf (pentane/Et2O 1:1) 0.43. [a]rD:t: ¼ ꢀ70.1 (c ¼ 0.8,
CHCl3). IR (CHCl3): 3361w, 3298w, 3062w, 3039w, 2991w, 2936w, 2532w, 1955w, 1890w, 1810w, 1582w,
1496m, 1447m, 1371s, 1178m, 1144m, 1087m, 1065m, 1037m, 958m, 878m. 1H-NMR (400 MHz, CDCl3):
0.86 (s, Me); 1.09 (s, Me); 3.94 (d, J ¼ 8.0, CH); 4.54 (d, J ¼ 8.0, CH); 7.06 – 7.10 (m, 2 arom. H); 7.19 – 7.29
(m, 8 arom. H); 7.38 – 7.45 (m, 8 arom. H); 7.63 – 7.68 (m, 2 arom. H). 13C-NMR (100 MHz, CDCl3): 26.67,
26.96 (Me); 62.13, 68.68 (C); 79.31, 81.34 (CH); 108.56, 119.23 (q, 1J(C,F) ¼ 323, CF3) (C); 126.95, 126.97,
127.29, 127.50, 127.63, 128.07, 128.12, 128.58, 129.29, 129.72, 130.76 (CH); 138.44, 139.13, 140.16, 148.86
(C). 19F-NMR (282 MHz, CHCl3): ꢀ 77.23. EI-MS: 597 (0.1, [M þ 1]þ), 209 (4.7), 208 (30.0), 207 (11.7),
196 (10.3), 183 (18.7), 182 (100), 180 (15.6), 179 (11.8), 178 (8.1), 167 (5.1), 165 (5.0). Anal. calc. for
C32H31F3N2O4S (596.67): C 64.42, H 5.24, N 4.69, S 5.37; found: C 64.37, H 5.47, N 4.71, S 5.51.
Preparation of 5 – 7 by Treatment of TADDAMIN 3 with TfCl. General Procedure (GP). To a soln. of
3 (1 equiv.) in CH2Cl2 (0.35m) was added the indicated base (4.5 equiv.), and the mixture was cooled to
ꢀ 408. TfCl (4 equiv.) was added dropwise, and the mixture was allowed to warm to r.t. (ca. 4 h). After
stirring at r.t. for 0.5 – 98 h, the reaction was quenched with 1n HCl soln., the org. layer was separated, and
the aq. phase was extracted with Et2O (3ꢁ). The combined org. layers were washed with sat. aq. NaCl

Helvetica Chimica Acta – Vol. 95 (2012)
1319
Table 2. Reactions of the TADDAMIN 3 with CF3SO2Cl (Tf-Cl)/DIPEA (Entries 1 – 6) or DBU
(Entry 7) in CH2Cl2 According to the GP. The reactions were followed by TLC analysis of withdrawn
samples. In most cases, the starting material 3 had disappeared, when room temperature was reached
(exceptions, see Entries 1 and 4). The crude product mixtures were subjected to (sometimes multiple)
FC. The yields given herein are those of the products obtained from the various FC fractions.
Entry Equiv.
CF3SO2Cl
Warm-up time/Time at r.t. [h] Isolated products
(Yield [%])
1
2
3
4
5
6
7b)
2
4
4
2.2
4
1/0.5
4/16
4/4
4/ –
4/98
4/6
3 (60), (RS )-6 (4), (SS )-6 (4), n.i.p.a) (15)
5 (24), (RS )-6 (12), (SS )-6 (14)
5 (26), (RS )-6 þ (SS )-6 (52), n.i.p. (10)
3 (29), 5 (12), n.i.p. (5)
5 (19), (SS )-6 (11), n.i.p. (35)
5 (28), (RS )-6 (15), (SS )-6 (13), 7 (5), n.i.p. (22)
5 (5), (RS )-6 (39), (SS )-6 (27), n.i.p. (7)
4
4
4/15
a) Not identified products. b) DBU instead of DIPEA.
soln., dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by
FC.
For a compilation of the experiments performed, see Table 2. The experiment of Entry 6 is detailed in
the following procedure for the isolation of 5, 6, and 7.
(3aS,8aS)-Hexahydro-2,2-dimethyl-4,4,8,8-tetraphenyl-1,3-dioxolo[4,5-d][1,2,7]thiadiazepine 6,6-Di-
oxide (5) and (SS)-N-[{(4S,5S)-5-[({[Bis(1-methylethyl)amino]methyl}amino)(diphenyl)methyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}(diphenyl)methyl]-1,1,1-trifluoromethanesulfinamide (7; Table 2, Entry 6).
TADDAMIN 3 (4.65 g, 10.0 mmol) in CH2Cl2 (27 ml) was treated with EtNiPr2 (7.50 ml, 45.0 mmol)
and TfCl (4.24 ml, 40.0 mmol) according to the GP (stirring at r.t. for 6 h). The residue (7.23 g), a mixture
of at least six products (Rf (pentane/Et2O 1:1) 0.80, 0.73, 0.66, 0.52, 0.36, 0.10), was purified by FC (SiO2
(40 cm ꢁ 50 mm); pentane/Et2O 1:1 ! 1:2). The Fractions (40 ml each) 2 – 20 yielded a mixture of six
products (3.25 g), and Frs. 21 – 50 afforded 5 (1.46 g, 28%). A second FC (SiO2 (35 cm ꢁ 50 mm);
pentane/Et2O 1:1) of the product mixture yielded, in Frs. (each 40 ml) 15 – 22, 7 (0.35 g, 5%).
Data of 5. Colorless powder. M.p. 265 – 2678. Rf (pentane/Et2O 1:6) 0.38. [a]rD:t: ¼ ꢀ183.4 (c ¼ 0.64,
CHCl3). IR (CHCl3): 3362w, 3063w, 3007w, 2937w, 1960 w, 1900w, 1810w, 1600w, 1496m, 1447m, 1423m,
1383m, 1372m, 1330m, 1161s, 1087m, 1064m, 1020m, 933m, 914m. 1H-NMR (400 MHz, CDCl3): 0.78 (s,
2 Me); 5.40 (s, 2 CH); 5.51 (br. s, 2 NH); 7.34 – 7.22 (m, 12 arom. H); 7.44 – 7.38 (m, 4 arom. H); 7.59 – 7.50
(m, 4 arom. H). 13C-NMR (100 MHz, CDCl3): 26.44 (Me); 67.10 (C); 80.40 (CH); 110.93 (C); 127.43,
127.56, 127.77, 128.49, 129.92 (CH); 139.98, 145.54 (C). MALDI-TOF-MS: 1075 ([2 M þ Na]þ), 549
([M þ Na]þ). EI-MS: 526 (0.01, Mþ), 281 (7), 224 (6), 223 (9), 222 (17), 207 (12), 194 (12), 183 (15), 182
(100), 180 (29). Anal. calc. for C31H30N2O4S (526.66): C 70.70, H 5.74, N 5.32, S 6.09; found: C 70.53, H
5.81, N 5.25, S 6.03.
Data of 7. Greenish foam. M.p. 203 – 2068. Rf (pentane/Et2O 3 :1) 0.55. [a]rD:t: ¼ ꢀ41.7 (c ¼ 0.93,
1
CHCl3). H-NMR (400 MHz, CDCl3): 10.65 (br. s, NH); 6.52 (s, 1 H); 4.92 (br. s, 1 H); 4.30 (d, J ¼ 8,
CH); 3.98 (d, J ¼ 8, CH); 3.38 (br. s, 1 H); 1.19 (s, Me); 1.16 (s, Me); 0.88 (d, J ¼ 7, 4 Me ) . 13C-NMR
(100 MHz): 154.9; 145.9; 143.3; 141.6; 140.1; 130.6; 130.1; 129.7; 127.9; 127.8; 127.7; 127.5; 127.0; 126.9;
126.6; 124.3 (q, J ¼ 333, CF3); 107.1; 82.8; 70.7; 69.3; 27.2; 27.1; 22.3; 14.1.
(RS)- and (SS)-N-[{(4S,5S)-5-[(Amino)(diphenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}(diphen-
yl)methyl]-1,1,1-trifluoromethanesulfinamide ((RS)-6 and (SS)-6, resp.; Table 2, Entry 7). TADDAMIN
3 (0.93 g, 2.00 mmol) in CH2Cl2 (6 ml) was treated with DBU (1.35 ml, 9.0 mmol) and TfCl (0.85 ml,
8.00 mmol) according to GP (stirring at r.t. for 15 h). The residue was purified by FC (2 ꢁ ; 1. SiO2 (60 g);
pentane/Et2O 1:1; 2. SiO2 (60 g); pentane/Et2O 6 :1) to afford (RS)-6 (0.45 g, 39%) and (SS)-6 (0.31 g,
27%).

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Helvetica Chimica Acta – Vol. 95 (2012)
Data of (RS)-6. White foam. M.p. 194 – 1958. Rf (pentane/Et2O 6 :1) 0.27. [a]rD:t: ¼ ꢀ48.8 (c ¼ 0.62,
CHCl3). IR (CHCl3): 3363w, 3290w, 3060w, 3007m, 2745w, 1950w, 1890w, 1810w, 1581w, 1495m, 1446m,
1382w, 1372w, 1172s, 1153s, 1082m, 1032w, 955w, 891w, 638w. 1H-NMR (400 MHz, CD2Cl2): 0.85 (s, Me);
1.25 (s, Me); 2.34 (br. s, NH2); 4.01 (d, J ¼ 8.0, CH); 4.66 (d, J ¼ 8.0, CH); 7.09 – 7.41 (m, 16 arom. H);
7.47 – 7.51 (m, 2 arom. H); 7.56 – 7.60 (m, 2 arom. H); 11.34 (br. s, NH). 13C-NMR (100 MHz, CD2Cl2):
26.76, 27.38 (Me); 62.98, 67.44 (C); 80.72, 82.67 (CH); 108.66, 125.53 (q, 1J(C,F) ¼ 317, CF3) (C); 127.29,
127.41, 127.77, 128.05, 128.10, 128.15, 128.48, 128.69, 128.92, 129.27, 130.56, 131.31 (CH); 140.12, 140.88,
142.22, 150.58 (C). 19F-NMR (282 MHz, CHCl3): ꢀ 76.90. MALDI-TOF-MS: 603 ([M þ Na]þ). Anal.
calc. for C32H31F3N2O3S (580.67): C 66.19, H 5.38, N 4.82; found: C 66.27, H 5.28, N 4.86.
Data of (SS)-6. White foam. M.p. 204 – 2068. Rf (pentane/Et2O 6 :1) 0.11. [a]rD:t: ¼ ꢀ61.1 (c ¼ 1.61,
CHCl3). IR (CHCl3): 3359w, 3295w, 3061w, 3007m, 2778w, 1950w, 1890w, 1810w, 1599w, 1582w, 1496m,
1447m, 1382m, 1371m, 1170s, 1153s, 1083s, 1032m, 956w, 890m, 867w, 634w. 1H-NMR (400 MHz, CDCl3):
0.88 (s, Me); 1.27 (s, Me); 2.23 (br. s, NH2); 3.88 (d, J ¼ 8.2, CH); 4.41 (d, J ¼ 8.2, CH); 7.03 – 7.07 (m, 2
arom. H); 7.10 – 7.30 (m, 8 arom. H); 7.33 – 7.49 (m, 8 arom. H); 7.77 – 7.82 (m, 2 arom. H); 10.95 (br. s,
NH). 13C-NMR (100 MHz, CDCl3): 26.73, 27.35 (Me); 62.81, 68.94 (C); 80.61, 83.39 (CH); 108.54, 125.12
1
(q, J(C,F) ¼ 334, CF3) (C); 127.20, 127.29, 127.67, 128.10, 128.17, 128.45, 128.52, 128.73, 129.80, 130.11,
130.22 (CH); 140.31, 141.11, 141.49, 150.33 (C). 19F-NMR (282 MHz, CHCl3): ꢀ 77.81. MALDI-TOF-
MS: 603 ([M þ Na]þ). Anal. calc. for C32H31F3N2O3S (580.67): C 66.19, H 5.38, N 4.82, S 5.52; found: C
66.43, H 5.52, N 4.90, S 5.52.
3. Preparation of the P-Containing Compounds 2a, 8, 9, and 10. (3aR,8aR)-Tetrahydro-6-hydroxy-
2,2-dimethyl-4,4,8,8-tetraphenyl-1,3-dioxolo[4,5-e][1,3,2]dioxaphosphepin 6-Oxide (2a). To a soln. of
(3aR,8aR)-6-Chlorotetrahydro-2,2-dimethyl-4,4,8,8-tetraphenyl-1,3-dioxolo[4,5-e][1,3,2]dioxaphosphe-
pin 6-oxide (8b; 547 mg, 1.00 mmol) [16b] in THF (10 ml) at r.t. was added H2O (10 ml), and the mixture
was heated for 24 h under reflux. The solvents were removed under reduced pressure, and the residue was
dissolved in CH2Cl2 (10 ml). Hexane (20 ml) was added at r.t., and the soln. was cooled to ꢀ 508,
whereby precipitation occurred. The solid was collected by filtration, washed with cold (ꢀ 508) CH2Cl2/
hexane 1:2, and co-evaporated with CH2Cl2 (5ꢁ). Drying of the residue in h.v. afforded 2a (372 mg,
70%) as an inclusion compound with THFand hexane (2a · 0.05 C4H8O · 0.21 C6H14). Colorless solid. M.p.
155 – 1588. [a]Dr:t: ¼ ꢀ216.0 (c ¼ 1.01, CHCl3). IR (CHCl3): 2933w, 1496m, 1448m, 1373w, 1215m, 1166m,
1
997s, 940s, 900w, 741s, 725m, 694s, 640w. H-NMR (400 MHz, CDCl3): 0.67 (s, Me); 4.64 (br. s, POH);
5.23 (s, CH); 7.21 – 7.42 (m, 16 arom. H); 7.54 – 7.60 (m, 4 arom. H). 13C-NMR (100 MHz, CDCl3): 26.6
(Me); 79.4 (CH); 88.0 (d, 2J(C,P) ¼ 6.4); 113.7 (C); 126.9, 127.2, 127.6, 128.1, 128.2, 128.7, 139.5 (d,
3
3J(C,P) ¼ 9.0, C); 143.3 (d, J(C,P) ¼ 2.2, C). 31P-NMR (162 MHz, CDCl3): ꢀ 8.08. MALDI-TOF-MS:
551.1606 ([M ꢀ Na]þ). Anal. calc. for C31H29O6P · 0.05 C4H8O · 0.21 C6H14 (550.24): C 70.86, H 5.92;
found: C 70.64, H 6.03. The anal. data are in agreement with those reported in [29].
(3aR,8aR)-6-Chlorotetrahydro-4,4,8,8-tetraphenyl-1,3-dioxolo[4,5-e][1,3,2]dioxaphosphepin 6-Ox-
ide (8a). To a soln. of TADDOL A (R1 ¼ R2 ¼ H, R3 ¼ Ph) [31b] (1.10 g, 2.50 mmol) in THF (13 ml)
was added BuLi (3.44 ml, 11.0 mmol) at ꢀ 788. The mixture was allowed to warm to r.t. and stirred for
1 h, before it was cooled again to ꢀ 788 and combined with POCl3 (0.30 ml, 3.25 mmol). The mixture was
stirred for 3 h at ꢀ 788, the reaction was quenched with sat. aq. NaHCO3 soln., and the mixture was
diluted with Et2O. The org. layer was washed with sat. aq. NaHCO3 soln., dried (MgSO4), filtered, and
the solvent was removed under reduced pressure. The residue was purified by FC (hexane/AcOEt 1:10)
to afford (next to an unidentified side-product) 8a (507 mg, 39%). Colorless solid. M.p. 135 – 1388. Rf
(hexane/AcOEt 4 :1) 0.30. [a]rD:t: ¼ ꢀ174.8 (c ¼ 1.01, CHCl3). IR (CHCl3): 2871w, 1495m, 1448m, 1297s,
1164w, 1091w, 1055w, 995s, 907s, 863w, 726s, 695s, 657w, 639w, 625w. 1H-NMR (400 MHz, CDCl3): 4.21 (s,
CHH); 4.55 (s, CHH); 5.15 (d, J ¼ 7.3, CH); 5.34 (d, J ¼ 7.3, CH); 7.31 – 7.42 (m, 12 arom. H); 7.45 – 7.48
3
(m, 4 arom. H); 7.53 – 7.66 (m, 4 arom. H). 13C-NMR (100 MHz, CDCl3): 78.6 (d, J(C,P) ¼ 2.2); 80.0,
90.6 (d, 2J(C,P) ¼ 10.5); 91.1 (d, 2J(C,P) ¼ 9.9); 96.6 (C); 126.7, 127.1, 127.6, 127.7, 127.8, 128.0, 128.1, 128.2,
128.4, 128.5, 128.5, 128.8, 137.5 (d, 3J(C,P) ¼ 7.6, C); 137.8 (d, 3J(C,P) ¼ 8.9, C); 141.4 (d, 3J(C,P) ¼ 2.6, C);
142.0 (d, 3J(C,P) ¼ 4.4, C). 31P-NMR (162 MHz, CDCl3): ꢀ 10.4. HR-MALDI-MS: 541.0943 ([M þ
Na]þ).
1,1,1-Trifluoro-N-[(3aR,8aR)-tetrahydro-6-oxido-4,4,8,8-tetraphenyl-1,3-dioxolo[4,5-e][1,3,2]diox-
aphosphepin-6-yl]methanesulfonamide N-Ethyl-N-(1-methylethyl)propan-2-amine Salt (9a) and the Salt-

Helvetica Chimica Acta – Vol. 95 (2012)
1321
Table 3. Crystallographic Data for 1, (SS )-6, 7, 9a, and 10
1
(SS )-6
7
9a
10
Formula
C39H41F3O7 C32H31F3N2O3S C43H56F3N3O4S C45H52F3N2O7PS C31.80H33.20NO6P
Formula weight
[g/mol]
678.72
580.65
767.97
852.92
556.37
T [K]
Wavelength [ꢄ]
Source
200(2)
1.54184
CuKa
203(2)
1.54184
CuKa
293(2)
0.71073
MoKa
100(2)
0.71073
MoKa
100(2)
1.54178
CuKa
Crystal dimensions 0.4 ꢁ 0.3 ꢁ 0.3 0.2 ꢁ 0.2 ꢁ 0.1 0.35 ꢁ 0.15 ꢁ 0.15 0.12 ꢁ 0.10 ꢁ 0.01 0.09 ꢁ 0.09 ꢁ 0.01
[mm]
Crystal system
Space group
q Range [8]
a [ꢄ]
b [ꢄ]
c [ꢄ]
triclinic
P1
monoclinic
P21
orthorhombic
P212121
triclinic
P1
monoclinic
P21
4.4 < q < 68.9 4.2 < q < 67.9 1.5 < q < 25.0
2.67 < q < 26.52 2.78 < q < 66.95
9.339(1)
9.836(1)
10.636(2)
70.11(1)
79.46(1)
77.07(1)
889.4(2)
1
9.371(1)
14.735(2)
10.513(2)
90
94.80(1)
90
1446.6(4)
2
1.333
11.170(3)
14.163(5)
27.019(14)
90
90
90
4274(3)
4
1.193
0.131
4244
10.2943(13)
10.6110(14)
11.7055(16)
88.716(4)
66.831(4)
69.433(4)
1090.6(2)
1
9.7089(4)
18.4783(9)
15.8813(8)
90
91.582(4)
90
2848.1(2)
4
1.298
a [8]
b [8]
g [8]
V [ꢄ3]
Z
1calc. [g cmꢀ3
]
1.267
0.805
1.299
0.175
12505
m [mmꢀ1
]
1.468
2757
1.230
13332
Total reflections 3515
measured
Independent
reflections
Reflections
observed
3515
2455
2286
4217
2709
6311
4036
6553
5680
3502
No. of variables
Criterion
Final R [%]
wR2 [%]
447
I > 3s(I)
3.66
12.98
1.367
377
I > 3s(I)
6.26
20.91
1.891
454
I > 3s(I)
5.58
15.51
1.398
586
I > 2s(I)
5.39
11.41
1.010
758
I > 2s(I)
5.98
15.87
1.153
Goodness-of-fit
D1 (max, min)
0.244, ꢀ 0.197 0.887, ꢀ 0.631 0.254, ꢀ 0.421
0.366, ꢀ 0.484
0.718, ꢀ 0.355
[e ꢄꢀ3
]
CCDC No.
157928 157929 867042
871617
870465
Free Imide 9b. A mixture of 8a (104 mg, 0.2 mmol), trifluoromethanesulfonamide (59.6 mg, 0.4 mmol),
and EtNiPr2 (155 mg, 1.2 mmol) in CDCl3 (0.3 ml) was stirred at 558 for 14 h in a sealed vial. The mixture
was allowed to cool to r.t. and was then directly purified by FC (hexane/AcOEt 1:1) to afford 9a
(43.4 mg, 34%). Colorless solid. M.p. 234 – 2368. Rf (hexane/AcOEt 1:2) 0.35. [a]rD:t: ¼ ꢀ58.0 (c ¼ 1.01,
CHCl3). IR (CHCl3): 2996w, 1495m, 1449m, 1396w, 1305s, 1258s, 1203s, 1166s, 1088s, 1055m, 1039m,
1009s, 956s, 9001m, 888m, 789m, 736s, 698s. 1H-NMR (400 MHz, CDCl3): 0.83 (t, J ¼ 7.4, Me); 0.86 – 0.95
(m, 12 H, Me); 2.40 – 2.56 (m, 2 H, CH2); 2.83 – 2.98 (m, 2 H, CH); 3.69 (s, 1 H, CH2); 4.63 (d, J ¼ 7.6,
CH); 5.06 (s, 1 H, CH2); 5.82 (d, J ¼ 7.6, CH); 7.18 – 7.67 (m, 12 arom. H); 7.44 – 7.59 (m, 4 arom. H);
7.68 – 7.80 (m, 4 arom. H). 13C-NMR (100 MHz, CDCl3): 11.0 (Me); 17.6 (4 Me); 40.8 (CH2); 52.5 (2 CH),
77.9 (d, 3J(C,P) ¼ 1.84, CH); 83.6 (CH); 84.1 (d, 2J(C,P) ¼ 7.3); 84.7 (d, 2J(C,P) ¼ 6.1); 95.6 (CH2); 120.8
(q, 1J(C,F) ¼ 322.7); 127.2, 127.3, 127.3, 127.5, 127.7, 127.7, 127.8, 127.9, 128.3, 139.3 (d, 3J(C,P) ¼ 10.6, C);
141.2, 144.3 (d, 3J(C,P) ¼ 12.5, C); 145.6, 171.2. 19F-NMR (376 MHz, CDCl3): ꢀ 78.9. 31P-NMR
(162 MHz, CDCl3): ꢀ 10.0. HR-MALDI-MS: 630.0967 ([M ꢀ H]ꢀ).

1322
Helvetica Chimica Acta – Vol. 95 (2012)
Data of 9b. To obtain a sample of the salt-free compound, 9a was subjected to prep. TLC (CH2Cl2/
MeOH 10 :1). Colorless wax. Rf (CH2Cl2/MeOH 15 :1) 0.25. 1H-NMR (400 MHz, CDCl3): 3.66 (s, 1 H,
CH2); 4.61 (d, J ¼ 7.6, CH); 5.08 (s, 1 H, CH2), 5.86 (d, J ¼ 7.6, CH); 7.19 – 7.62 (m, 12 arom. H); 7.45 –
7.52 (m, 2 arom. H); 7.53 – 7.62 (m, 2 arom. H); 7.68 – 7.74 (m, 2 arom. H); 7.76 – 7.82 (m, 2 arom. H). 19F-
NMR (376 MHz, CDCl3): ꢀ 78.9. 31P-NMR (162 MHz, CDCl3): ꢀ 10.0.
(3aR,8aR)-Tetrahydro-2,2-dimethyl-4,4,8,8-tetraphenyl-1,3-dioxolo[4,5-e][1,3,2]dioxaphosphepin-
6-amine 6-Oxide (10). To a soln. of 8b (54.7 mg, 100 mmol) [16b] in THF (2.0 ml) was added at r.t. aq.
NH3 soln. (2.0 ml, 24 %), and the mixture was stirred at r.t. for 60 h. The solvents were removed under
reduced pressure, and the residue was co-evaporated with CH2Cl2 (5ꢁ). Drying of the residue in h.v.
afforded 10 (50.5 mg, 96 %). Colorless solid. M.p. 3128 (dec.). [a]rD:t: ¼ ꢀ200.8 (c ¼ 1.00, CHCl3). IR
(CHCl3): 3063w, 1559w, 1495m, 1448m, 1383w, 1249m, 1218m, 1165m, 1089m, 1057s, 998s, 935w, 903s,
725s, 696s, 642w. 1H-NMR (400 MHz, CDCl3): 0.65 (s, Me); 0.71 (s, Me); 2.82 (br. s, NH2); 5.25 (J ¼ 8.1,
CH); 5.41 (J ¼ 8.1, CH); 7.23 – 7.46 (m, 14 arom. H); 7.49 – 7.53 (m, 2 arom. H); 7.59 – 7.65 (m, 4 arom.
H). 13C-NMR (100 MHz, CDCl3): 26.4 (Me); 26.7 (Me); 79.0 (d, 3J(C,P) ¼ 1.1); 79.5 (d, 3J(C,P) ¼ 1.4);
86.5 (d, 2J(C,P) ¼ 5.9); 88.4 (d, 2J(C,P) ¼ 8.6); 113.8 (C); 127.0, 127.2, 127.3, 127.6, 127.6, 127.9, 128.1, 128.2,
3
3
128.3, 128.4, 128.5, 129.2, 139.8 (d, J(C,P) ¼ 6.3, C); 140.0 (d, J(C,P) ¼ 10.6, C); 143.4 (C); 144.2 (d,
3J(C,P) ¼ 3.8, C). 31P-NMR (162 MHz, CDCl3): ꢀ 0.26. HR-ESI-MS: 528.1955 ([M þ H]þ).
*
4. pKMCS Measurements. The measurements were carried out in degassed solvent (2-methoxyethanol
(ꢁmethylcellosolveꢂ, MCS)/H2O 80 :20) at 258 under Ar. Before titration, the electrode was calibrated by
*
a three-point calibration (pH 4, 7, and 9). As reference compounds PhCO2H (pKMCS ¼ 6.63) or 2-
*
IꢀC6H4CO2H (pKMCS ¼ 5.73) were used; a deviation of up to 0.08 pK units was considered acceptable.
*
The titration was carried out with Me4NOH with a continuous addition mode. pKMCS Values in the range
between 3 and 12 can be determined by the method; for a detailed description of the method, see [54],
*
and for a comprehensive collection of pKMCS values determined this way see [55].
5. X-Ray Data. See Table 3.
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Received March 23, 2012